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TRANSCRIPT
PRIMARY MANUFACTURING
PARENTERAL FORMULATION,
FILTERING, AND FILLING
Learning Objectives
By the completion of this lecture and lab exercise, the
participant will be able to:
• List some of the unique requirements in a CGMP environment designed to formulate, filter, and fill parenteral drugs and combination devices.
• Discuss how CGMP regulatory requirements & aseptic processing help protect sterile products and the patients who use them.
Learning Objectives
By the completion of this lecture and lab exercise, the
participant will be able to:
• Identify forms that parenteral formulations may take.
• Describe some different filling mechanisms and some of the pros and cons of each.
Learning Objectives
By the completion of this lecture and lab exercise, the
participant will be able to:
• Compare filter testing by Bubble point and diffusive flow (lab exercise).
• Discuss some of the issues and challenges related to filtering.
Learning Objectives
By the completion of this lecture and lab exercise, the
participant will be able to:
• Describe some of the challenges related to sealing, stoppering, and capping parenteral products.
A Few Key Terms
Parenteral Drugs: Drugs administered by injection into a
vein, muscle, or subcutaneous tissue.
A Few Key Terms
Aseptic Processing: the processes by which
sterile products are filled and packaged in a
manner that maintains sterility.
Bioburden: Degree of microbial
contamination or microbial load; the number
of microorganisms contaminating an object.
A Few Key Terms
CGMP: Current Good Manufacturing
Practices, regulatory requirements designed
to protect product SISPQ (Safety, Identity,
Strength, Purity, Quality) and to maintain the
CGMP environment in a consistent State of
Control, in accordance to pre-determined
Quality standards and systems.
Unique Requirements When
Formulating or Filling Sterile Drugs
One Challenge Related to Aseptic Processing of Parenterals
After medical devices are
assembled and packaged, they are
usually sterilized by a variety of
methods, including autoclaves and
radiation. This intense sterilization
is done at the very end of the
production process, which is why it
is called “terminal sterilization”.
One Challenge Related to Aseptic Processing of Parenterals
Unfortunately, extreme heat and
radiation would cause most
parenteral drugs to deteriorate,
which means that the drugs might
not be as effective or safe as they
were intended to be.
For that reason, processes are put
into place to ensure sterility at each
stage of production of parenteral
drugs.
One Challenge Related to Aseptic Processing of Parenterals
A final filtration is designed to screen out microbes and
particulates. Here is one filtering approach as illustrated by
Amazon filters UK. We will learn more about filtering later.
Parenteral Production – A Unique Environment
Exercise 1: Using what you’ve learned so far (and just common
sense), what do you think some requirements might be for
personnel who are working in parenteral manufacturing and for
the rooms and equipment used to formulate, filter, and fill
parenterals?
If I worked in parenteral primary production, I would need to
know how to….
I imagine that some requirements related to the rooms and
equipment used to produce parenterals include…..
CGMP Requirements & Aseptic Processing
Forms of Parenteral Drugs
Liquid Solutions
Emulsions or Suspensions
Lyophilized Forms of Injectable Drugs
+
"Nicoderm". Licensed under CC BY 2.5 via Wikimedia Commons -https://commons.wikimedia.org/wiki/File:Nicoderm.JPG#/media/File:Nicoderm.JPG
Trans-Dermal Patch
Formulation
The topic of parenteral drug formulation
requires several semester-length courses to
full understand, but take a look at your
process map titled “Parenteral Drug
Formation – A Big Picture View”.
It provides a big-picture view of many of the
topics and challenges that are addressed
during formulation.
A Big Picture View of Formulation
A Big Picture View of the Filtration Process
Filtration of Parenterals
Most of us are familiar with the use of filters when preparing a pot of coffee.
What do you think might be some differences between a filter used for brewing coffee and a filter used to purify large amounts of pharmaceutical parenteral solutions (formulated bulk solution)?
• Pharmaceutical filter is sterile, in a sterile system
• The holes in pharmaceutical filters are MUCH smaller
• Protection against contaminants & harmful microbes –impacts patient safety, not just a better-tasting coffee
Filtration of Parenterals During Formulation
Some of the purposes of early filtration are described on the next slide…
Filtration of Parenterals During Formulation
Filtration through a membrane and/or filtering processes using
compressed gas and air are used in pharmaceutical manufacturing
to remove unwanted material from the formulated bulk solution.
The first step in any filtration process is the removal of the largest
suspended matter, either organic or inorganic.
• Serves to clarify the solution.
• Makes further processing more efficient by removing
substances that might interfere with those processes.
• Helps protect expensive downstream equipment & the final
sterilization filter from unnecessary damage from large
particles.
Filtration of Parenterals
Final sterilization plays an essential role by removing undesirable
elements (harmful microbes, particulates, etc.) while maintaining the
identity and strength of the final product.
• Separates microbes & particulates from the rest of the product
• Size of filter pores based on size of possible contaminants
The Filtering Process
Courtesy of EMD Millipore
Strict Regulatory Controls Related to Filtering of Parenterals
Stringent Regulatory Controls Related to Sterile Filters
Manufacturers who filter parenterals during aseptic processing must be able to demonstrate that:
• The company has scientific documentation of the levels and effects of the pre-filtration bioburden.
• The sterile condition of the filter, its housing and associated tubing has been scientifically qualified (usually by the manufacturer of the filters and related components).
• Validation studies demonstrate that the combination of the filter, product, and processing conditions results in a sterile filtrate (sterile, filtered product). This is done by the manufacturer of the parenteral drugs.
Source: Provantage Services & EMD Millipore, 2014
Types of Sterile Filters
Categorization Based on Size of Pores in Membrane
Filter Type Size Range (microns)
Examples of What Is Removed by this Filter Type
Particle 10 to 200 • Pollens• Particles• Some bacteria
Microfilter 0.1 to 10 • All bacteria• Yeasts• Colloids
Ultrafilter 0.001 to 0.1 • Most viruses• Large organic compounds (> 10,000
DaltonsNanofilter (Reverse Osmosis)
Less than 0.001 • Small organic compounds• Ions
Microfilters
• Porosity of microfilters range from 0.1m to 10 m
• Used to remove all bacteria, yeast & colloidal forms
• Can be integrity testedExamples: Millipore Express SHC 0.5 / 0.2 µ m PES filters
Categorization Based on Behavior with Water
Hydrophobic
These Millex filter units with hydrophobic Fluoropore membrane are used for sterilizing gases, venting sterile containers, and sterilizing or clarifying organic solutions.
Example of Hydrophobic Stacked Disc Membrane
Categorization Based on Behavior with Water
Example: Durapore 0.45 µm Hydrophilic Cartridge Filter
Hydrophilic
More about Filter Testingand Validation
Destructive & Non-Destructive Testing
Key Term – Microbial retention
• The ability of a filter to remove bacteria from the filtrate, thereby providing a sterile solution.
Destructive Testing
• Used to qualify filter initially• Includes three main tests:
Bacterial retention using actual final formulation of the parenteral product
Filter extractables / leachables Compatibility of filter with parenteral product
Non-Destructive Testing – testing prior to and after using the filter in batch production (Typically bubble-point and diffusive flow)
Question: Why do you think a non-destructive method is used during production?
Integrity Testing
Bubble point testing
Diffusive Flow testing
Surface Tension
Figures courtesy of EMD Millipore and WikiMedia
Automated filter Integrity Testing
Millipore Integritest 4 AFIT
Image courtesy of EMD Millipore Corporation,
Integritest is a registered trademark of Merck KGaA
Automated filter integrity testing has many advantages:
• Elimination of operator to operator variability.
• Increased sensitivity; you can easily determine the bubble-point of a large filter using AFIT, while it would be impossible to manually detect mass flow of gas (bubble-point) while the normal diffusive flow of the large membrane surface area is on-going.
• AFIT provides improved testing consistency and reproducible results.
Filtering Challenges
• Wetting- all of the filter’s pores must be filled with liquid
• Plugging- material in the product blocking the filter’s pores-stopping the flow
• Filter Failure
Integrity test suppression - False failure
Integrity test failure- the filter is damaged
Filling Mechanisms
A Big Picture View of Filling Operations
Look at your legal –sized, colored, two-sided illustration of syringe-filling and vial filling.
Possible Challenges Encountered During Filling
• Product splashing
• Product spills
• Product foaming and effect on dose accuracy
• Viscous product and potential problems with dose
accuracy and uniformity
• Out of tolerance fill volumes/weight
• Receiving vessel overflows
• Receiving vessel over-pressurized
• Filling needles are bent
• Filling needles are plugged with product
Possible Challenges Encountered During Filling
• Control of dose from container-to-container
• Adsorption of active ingredient on the
surface of the tubing used with the filling
machine.
• Protein aggregation due to tubing surface
interactions
• Leachables from tubing
• Fill pump leak
• Power outage
Different Approaches to Filling
Driving Device Filling Mechanisms
Gravity (solids and liquids)(oldest & most economical)
Gravimetric, time-pressure, fill by weight
Piston (liquids and gases) Rotary piston, Rolling diaphragm pump
Rotary pump (liquids and gases)
Rotary peristaltic
Auger screw or vibrator (solids)
Vibratory / Mechanical force
Gravimetric, time-pressure, fill by weight
Filling via Piston Pump
Courtesy of www.filamtic.com and www.pharmaceuticalonline.com
Rotary Pump Aseptic Filler
Courtesy of OverLook Industries and Optima Corporation
Peristaltic Filling
Courtesy of Colanar and www.contract pharmica.com
Includes single-use components.
Lyophilization
Exercise 2
Scenario: You are a new manager in a parenteral manufacturing company with aging equipment. Due to a recent round of retirements, many of your people are relatively inexperienced, so you are looking for something that is easy to maintain and change over. The Chief Financial Officer is especially sensitive about unexpected replacements of expensive parts. Some of your products include biologics. You are coming to realize that single-use components cut down the potential for contamination.
Based on the tables in Exercise 2 and this scenario, which filling method seems most attractive?
Sealing Mechanisms
Ampules – Sealed with a Flame
Courtesy of www.rotechmachinery.en.alababa.com
Vial Stoppers for Vials
Courtesy of Optima Corporation
Plungers for Syringes
Courtesy of Optima Corporation
Anatomy of a Pre-filled Syringe
Courtesy of www.drugs.com
Plunger Rods and Labels for Syringes
Courtesy of ima-pharma.com
Plunger Rod Insertion and Labeling Machine
Possible Challenges During Stoppering
• Too little or too much silicone on stoppers
• Misaligned or bent syringe stopper insertion rods or tubes
• Stoppers become jammed on the track
• Improper head space (syringes)
• Stoppers are not completely seated
Conclusion
Aseptic processing of parenterals involves a number of interesting challenges, including:
• Protecting the sterility of the product as it moves through several phases of formulation, filtering, filling, and packaging.
• Development of the experience and technical knowledge to trouble-shoot issues as they occur.
• Maintaining consistent compliance with CGMP regulatory requirements to protect product SISPQ.
Conclusion
There are also significant benefits related to successful parenteral drug production, including:
• Knowing that you helped produce medication that will save a life or will fight life-threatening diseases.
• Becoming a skilled employee with multiple options in the bio tech industry; an industry forecasted to continue to grow significantly in the future.
Any questions before we move on to the lab?